Children born to middle-aged men are more likely than those born to younger fathers to develop any of a range of mental difficulties, including attention deficits, bipolar disorder, autism and schizophrenia, according to the most comprehensive study to date of paternal age and offspring mental health.

In recent years, scientists have debated based on mixed evidence whether a father’s age is linked to his child’s vulnerability to individual disorders like autism and schizophrenia. Some studies have found strong associations, while others have found weak associations or none at all.

The new report, which looked at many mental disorders in Sweden, should inflame the debate, if not settle it, experts said. Men have a biological clock of sorts because of random mutations in sperm over time, the report suggests, and the risks associated with later fatherhood may be higher than previously thought.

The findings were published Wednesday in the journal JAMA Psychiatry.

“This is the best paper I’ve seen on this topic, and it suggests several lines of inquiry into mental illness,” said Dr. Patrick Sullivan, a professor of genetics at the University of North Carolina, who was not involved in the research. “But the last thing people should do is read this and say, ‘Oh no, I had a kid at 43, the kid’s doomed.’ The vast majority of kids born to older dads will be just fine.”

Dr. Kenneth Kendler, a professor of psychiatry and human molecular genetics at Virginia Commonwealth University, also urged caution in interpreting the results.

“This is great work from a scientific perspective,” he said. “But it needs to be replicated, and biomedical science needs to get in gear and figure out what accounts for” the mixed findings of previous studies.

The strengths of the new report are size and rigor. The research team, led by Brian D’Onofrio of Indiana University, analyzed medical and public records of some 2.6 million people born in Sweden from 1973 to 2001.

Compared with the children of young fathers, ages 20-24, those born to men age 45 and older had about twice the risk of developing psychosis, the signature symptom of schizophrenia; more than three times the likelihood of receiving a diagnosis of autism; and about 13 times the chance of having a diagnosis of attention deficit disorder. Children born to older fathers also tended to struggle more with academics and substance abuse.

The researchers controlled for every factor they could think of, including parents’ education and income. Older couples tend to be more stable and have more income — both protective factors that help to temper mental problems — and this was the case in the study. But much of the risk associated with paternal age remained.

The researchers say that any increased risk due solely to paternal age is most likely a result of the accumulation of genetic mutations in sperm cells. Unlike women, who age with a limited number of eggs, men have to replenish their supply of sperm cells. Studies suggest that the cells’ repeated reproductions lead to the accumulation of random errors over time, called de novo mutations. Most such mutations are harmless but some have been linked to mental disorders.

“It’s a plausible hypothesis at this point,” Sullivan said.

Experts say the numbers in the study look more alarming than they probably are. For example, Sullivan said, the overall prevalence of autism is 0.5 percent to 1 percent of the population, depending on the estimate and the location. But for the children of healthy parents in their 20s, the rate is perhaps 1 in 300, or even lower. A threefold increase would put the odds at about 1 in 100, still very low.

The same goes for psychosis. The baseline rate is tiny for the children of young, healthy parents, and remains quite low even when doubled.

The researchers found much larger increases in risk for attention deficits (13-fold) and bipolar disorder (25-fold) tied to late fatherhood.

“I don’t know what to do with those numbers,” Sullivan said, noting that two recent genetic studies found that the contribution of de novo mutations to the risk of mental disorders was “probably pretty low” compared with other factors.

“The question we now need to ask,” Kendler said, “is what else is going on with respect to older and younger siblings that could cause these differences.”

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